RhoA and Rac1 GTPases play major and differential roles in stromal cell-derived factor-1-induced cell adhesion and chemotaxis in multiple myeloma

被引：102

作者：

Azab, Abdel Kareem ^{[1
]}

Azab, Feda ^{[1
]}

Blotta, Simona ^{[1
]}

Pitsillides, Costas M. ^{[2
]}

Thompson, Brian ^{[2
]}

Runnels, Judith M. ^{[1
]}

Roccaro, Aldo M. ^{[1
]}

Ngo, Hai T. ^{[1
]}

Melhem, Molly R. ^{[1
]}

Sacco, Antonio ^{[1
]}

Jia, Xiaoying ^{[1
]}

Anderson, Kenneth C. ^{[1
]}

Lin, Charles P. ^{[2
]}

Rollins, Barrett J. ^{[1
]}

Ghobrial, Irene M. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA

来源：

BLOOD | 2009年 / 114卷 / 03期

关键词：

BONE-MARROW; ACTIN CYTOSKELETON; MIGRATION; FACTOR-1-ALPHA; INHIBITION; ACTIVATION; LOCOMOTION; SURVIVAL; VLA-4;

D O I：

10.1182/blood-2009-01-199281

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The interaction of multiple myeloma (MM) cells with the bone marrow (BM) milieu plays a crucial role in MM pathogenesis. Stromal cell-derived factor-1 (SDF1) regulates homing of MM cells to the BM. In this study, we examined the role of RhoA and Rac1 GTPases in SDF1-induced adhesion and chemotaxis of MM. We found that both RhoA and Rac1 play key roles in SDF1-induced adhesion of MM cells to BM stromal cells, whereas RhoA was involved in chemotaxis and motility. Furthermore, both ROCK and Rac1 inhibitors reduced SDF1-induced polymerization of actin and activation of LIMK, SRC, FAK, and cofilin. Moreover, RhoA and Rac1 reduced homing of MM cells to BM niches. In conclusion, we characterized the role of RhoA and Rac1 GTPases in SDF1-induced adhesion, chemotaxis, and homing of MM cells to the BM, providing the framework for targeting RhoA and Rac1 GTPases as novel MM therapy. (Blood. 2009; 114: 619-629)

引用

页码：619 / 629

页数：11

共 34 条

[21] The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia [J].

Leleu, Xavier ;

Jia, Xiaoying ;

Runnels, Judith ;

Ngo, Hai T. ;

Moreau, Anne-Sophie ;

Farag, Mena ;

Spencer, Joel A. ;

Pitsillides, Costas M. ;

Hatjiharissi, Evdoxia ;

Roccaro, Aldo ;

O'Sullivan, Garrett ;

McMillin, Douglas W. ;

Moreno, Daisy ;

Kiziltepe, Tanyel ;

Carrasco, Ruben ;

Treon, Steven P. ;

Hideshima, Teru ;

Anderson, Kenneth C. ;

Lin, Charles P. ;

Ghobrial, Irene M. .

BLOOD, 2007, 110 (13) :4417-4426

[22] CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion [J].

Libura, J ;

Drukala, J ;

Majka, M ;

Tomescu, O ;

Navenot, JM ;

Kucia, M ;

Marquez, L ;

Peiper, SC ;

Barr, FG ;

Janowska-Wieczorek, A ;

Ratajczak, MZ .

BLOOD, 2002, 100 (07) :2597-2606

[23] Signaling from rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase [J].

Maekawa, M ;

Ishizaki, T ;

Boku, S ;

Watanabe, N ;

Fujita, A ;

Iwamatsu, A ;

Obinata, T ;

Ohashi, K ;

Mizuno, K ;

Narumiya, S .

SCIENCE, 1999, 285 (5429) :895-898

[24] Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma [J].

Nowakowski, GS ;

Witzig, TE ;

Dingli, D ;

Tracz, MJ ;

Gertz, MA ;

Lacy, MQ ;

Lust, JA ;

Dispenzieri, A ;

Greipp, PR ;

Kyle, RA ;

Rajkumar, SV .

BLOOD, 2005, 106 (07) :2276-2279

[25] Targeting multiple myeloma cells and their bone marrow microenvironment [J].

Pagnucco, G ;

Cardinale, G ;

Gervasi, F .

SIGNAL TRANSDUCTION AND COMMUNICATION IN CANCER CELLS, 2004, 1028 :390-399

[26] Integrin α4β1 involvement in stromal cell-derived factor-1α-promoted myeloma cell transendothelial migration and adhesion:: role of cAMP and the actin cytoskeleton in adhesion [J].

Parmo-Cabañas, M ;

Bartolomé, RA ;

Wright, N ;

Hidalgo, A ;

Drager, AM ;

Teixidó, J .

EXPERIMENTAL CELL RESEARCH, 2004, 294 (02) :571-580

[27] Chemokine stromal cell-derived factor-1α modulates VLA-4 integrin-mediated multiple myeloma cell adhesion to CS-1/fibronectin and VCAM-1 [J].

Sanz-Rodríguez, F ;

Hidalgo, A ;

Teixidó, J .

BLOOD, 2001, 97 (02) :346-351

[28] VLA-4-dependent myeloma cell adhesion [J].

Sanz-Rodríguez, F ;

Teixidó, J .

LEUKEMIA & LYMPHOMA, 2001, 41 (3-4) :239-245

[29] In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment [J].

Sipkins, DA ;

Wei, XB ;

Wu, JW ;

Runnels, JM ;

Côté, D ;

Means, TK ;

Luster, AD ;

Scadden, DT ;

Lin, CP .

NATURE, 2005, 435 (7044) :969-973

[30] The Gα13-Rho signaling axis is required for SDF-1-induced migration through CXCR4 [J].

Tan, Wenfu ;

Martin, Daniel ;

Gutkind, J. Silvio .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (51) :39542-39549

← 1 2 3 4 →